Due to advances in conventional imaging, adrenal masses are detected with increasing frequency. The prevalence of incidentalomas, i.e. tumors found by coincidence without clinical symptoms or suspicion, is increasing with age.
Adrenal masses represent a wide range of different pathological entities, e.g. adrenal adenomas as prevalent form, adrenocortical carcinomas, hyperplasias, pheochromocytomas, ganglioneuromas, renal angiomyolipomas, lipomas, lymphangiomas, metastases as well as misinterpreted retroperitoneal neoplasias such as sarcomas or renal cell carcinomas. Accordingly, the different lesions require highly variable therapies ranging from immediate surgery to observational follow-up. Having a finding in the adrenal gland on diagnostic imaging, the clinician faces the challenge to decide whether the lesion is harmful and what therapy has to be chosen.
A particular challenge is the distinction whether the adrenal mass is of adrenocortical origin. About 80% of all adrenal masses do not show any endocrine activity which renders laboratory diagnostics difficult. A particular problem is the diagnosis of adrenocortical carcinomas. Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor associated with a bad prognosis for the patient. The 5-year overall survival rate for patients with ACC is about 40% and the median survival in patients with advanced disease (stage IV) is <1 year. In addition, one third of the patients are under the age of 30 years.
Conventional imaging provides only limited information about the origin of an adrenal lesion. Although both computerized tomography (CT) and magnetic resonance imaging (MRI) contribute significantly to the characterization of adrenal masses, they often fail to differentiate lesions with low fat content. In many cases neither CT nor MRI provide a clear diagnosis of an adrenal tumor.
A tumor biopsy may be needed to definitely characterize the origin of the tumor. However, in adrenocortical cancer this invasive procedure has been associated with a variety of adverse events. In particular, the risk for dissemination of tumor cells is very high leading to metastasis along the puncture channel.
Thus, noninvasive tools to characterize the tissue specificity of an adrenal lesion, in particular imaging tools for the diagnosis of adrenal masses, are of considerable interest. Furthermore, there is a need for an imaging method for monitoring and assessment of a cytotoxic therapy of adrenocortical carcinomas.
The presently available norcholesterol scintigraphy with [131I]iodomethyl norcholesterol (NP59) and [75Se]selenomethyl norcholesterol (Scintadren) is able to differentiate adrenal adenomas from other adrenal masses. However, the approach is time consuming and leads to a considerable patient radiation dose. Moreover, this technique is limited by poor spatial resolution and low specificity, because adrenal cancers may show highly variable uptake.
Recently, high-affinity binding of metomidate (MTO) to adrenal steroidogenic enzymes has led to its use as a radiotracer for adrenal steroidogenic tissue. Accordingly, [11C]MTO has been introduced as a tracer for positron emission tomography (PET), differentiating adrenocortical from nonadrenocortical tissue with high specificity. However, due to the short half-life of 11C of about 20 min, use of [11C]MTO-PET is restricted to PET centers with an on-site cyclotron. Moreover, the short half-life also limits its use to the early uptake of the tracer potentially missing the optimal target to background ratio. Therefore, more long-lived radionuclides and a better general availability of radiotracers for adrenocortical imaging are prerequisites for their successful use.
Hahner at al. (J. Clin. Endocrinol. Metab. June 2008, 93(6):2358-2365) have recently shown that iodometomidate (IMTO) binds to adrenal membranes with high affinity in vitro. Further, they have developed an in vivo detection system of adrenal enzymes 11β hydroxylase (Cyp11B1) and aldosterone synthase (CYP11B2) by [123I]IMTO scintigraphy both in animals and humans. Since these enzymes are located exclusively in adrenocortical tissue, the findings of Hahner et al. suggest that [123I]iodometomidate is a highly specific radiotracer for imaging of adrenocortical tissue.
In ACC, many patients have progressive disease despite standard treatment, indicating a need for new treatment options. Complete removal of the tumor is currently the best treatment option. But more than 80% of the patients receiving surgery with complete removal of the tumor develop a local recurrence and/or distant metastases. The only specific drug currently approved for the treatment of ACC is mitotane, which prolongs recurrence-free survival in an adjuvant setting. However, in advanced disease, it has an overall response rate of only 26% according to retrospective analyses. The combination of mitotane with etoposide, doxorubicin, cisplatin or streptozotocin is considered as current first-line therapy in metastatic ACC. However, response rates are low (25-50%). Accordingly, in many patients, salvage therapies are needed. So far, studies investigating targeted therapies in this patient population have been rather disappointing.
Recently it has been found that [131I]iodometomidate not only binds to Cyp11B1 and CYP11B2 with high specificity and affinity, but also high tracer uptake was observed in both primary tumor and metastases in patients with ACC. The therapeutic activity of [131I]IMTO radionuclide therapy has recently been assessed in patients with advanced ACC (Hahner et al, J. Clin. Endocrinol. Metab. March 2012, 97(3):914-922).
However, the biological half-life of IMTO in the blood of patients has been found to be very limited. Already after few minutes iodometomidate acid could be identified as a product of enzymatic hydrolysis. FIG. 1 shows the kinetics of metabolization of IMTO. In contrast to IMTO, iodometomidate acid has little or no affinity to the adrenal enzymes Cyp11B1 and CYP11B2, and it is released via the renal system.
Thus, there is a need for improved radiotracer compounds for diagnosis and treatment of adrenal masses, in particular adrenocortical carcinoma, which overcome the above-described shortcomings of the state of the art.